DESCRIPTION: The immune system has developed a number of mechanisms for recognizing foreign antigen while ignoring self-antigens. However, the presence of autoimmune diseases demonstrates these mechanisms can be bypassed. Our laboratory has demonstrated that the posttranslational modification of aspartic acid to isoaspartic acid in self-peptides induces immunogenicity to otherwise immunologically ignored peptides. Isoaspartyl residues occur spontaneously at physiological conditions and increase in aged or stressed cells. The proposed studies will examine how isoaspartyl containing self-peptides/proteins break tolerance and contribute to autoimmunity. This will be achieved by 1) examining T and B cell responses to isoaspartyl and normal forms of self-antigens, 2) determining the effect of isoaspartyl accumulation on immune function in mice deficient in the isoaspartyl repair enzyme PCMT, and 3) examining the spontaneous development of autoimmunity and pathology in PCMT -I- mice alone and backcrossed to a murine model of systemic lupus erythematosus (SLE). Results of these studies will be helpful in developing immunotherapies for the modulation of autoimmunity.